Therapeutic Apheresis and Dialysis 15(3):269–272doi: 10.1111/j.1744-9987.2011.00949.x 2011 The AuthorsTherapeutic Apheresis and Dialysis 2011 International Society for Apheresis
Partial Remission of Resistant Nephrotic Syndrome After
Matjaž Kopacˇ, Anamarija Meglicˇ, and Rina R Rus
Department of Nephrology, Division of Pediatrics, University Medical Centre Ljubljana, Ljubljana, SloveniaAbstract: Focal segmental glomerulosclerosis is sometimes
decreased by 50%. Seven months later, galactose was again
associated with a circulating permeability factor. It was
added for six months, after which proteinuria remained
proposed that this factor interacts with the sugars of the
below 2 g/24 h and the plasma albumin and cholesterol
glycocalyx, and its high affinity for galactose was shown on
concentrations normalized. An adolescent girl with a neph-
the basis of chromatographic studies. Galactose inactivates
rotic syndrome resistant to corticosteroids was admitted. A
it and seems to lead to its clearance from plasma. A toddler
renal biopsy revealed mesangioproliferative glomerulone-
with a nephrotic syndrome resistant to corticosteroids was
phritis with C1q nephropathy. Therapy with tacrolimus
admitted. A renal biopsy revealed minimal change disease
failed to induce remission. After six months, we added
with deposition of immunoglobulin M. Immunosuppressive
galactose for three months, which reduced proteinuria to
therapy with pulses of cyclophosphamide, low-dose combi-
0.76 g/24 h. After the discontinuation of galactose therapy,
nation immunosuppressive therapy, and later with myco-
proteinuria increased to 2.48 g/24 h, despite further treat-
phenolate mofetil failed to induce remission. A renal
ment with tacrolimus. It seems that oral galactose at a dose
biopsy six years later showed transformation to FSGS.
of 0.2 g/kg twice a day could be a promising new and non-
After unsuccessful treatment with monthly pulses of cyclo-
toxic therapy for the treatment of resistant nephrotic syn-
phosphamide, we began therapy with tacrolimus, which
Key Words: Focal segmental glomerulosclerosis,
showed no effect. After two months, we added oral galac-
Galactose, Immunosuppressive therapy, Nephrotic syn-
tose to tacrolimus for one month, after which proteinuria
Steroid-resistant nephrotic syndrome is a specific
cant decrease in permeability factor in a patient with
clinical phenomenon with a varied histological diag-
FSGS-PF-associated nephrotic syndrome, but with
nosis. One of these is focal segmental glomeruloscle-
no improvement in proteinuria, as the patient was
rosis (FSGS), which is the most frequently acquired
already dialysis-dependent (2). In another report,
disease resulting in end-stage renal disease in chil-
remission was achieved after galactose therapy in an
dren (1). FSGS is sometimes associated with a cir-
adult male with a nephrotic syndrome that was resis-
culating factor, called FSGS-permeability factor
tant to corticosteroids, other immunosuppression,
(FSGS-PF) (2). This disease often recurs after trans-
and plasmapheresis. The patient was given oral galac-
plantation (3). Savin et al. proved a high affinity of
tose as a last resort treatment, which was followed by
FSGS-PF for galactose, based on chromatographic
a long-standing remission of his nephrotic syndrome
studies. Galactose inactivates FSGS-PF and seems to
that correlated with the reduction of FSGS-PF activ-
lead to its clearance from plasma. In vivo administra-
tion of galactose has been associated with a signifi-
CASE REPORTSCase report 1
Address correspondence and reprint requests to Dr Matjaž
A three-year-old boy was admitted in June 2002
Kopacˇ, Department of Nephrology, Division of Pediatrics, Univer-sity Medical Centre Ljubljana, Bohoricˇeva 20, 1000 Ljubljana,
after failure to induce remission of nephrotic syn-
drome after four weeks of therapy with cortico-
Presented in part at the Symposium Celebrating the 40th Anni-
steroids in a regional hospital. A renal biopsy was
versary of Chronic Dialysis and Kidney Transplantation inSlovenia held 4–5 November 2010 in Bled, Slovenia.
performed and the findings were consistent with
CYCLOPHOSPHAMIDE T A C R O L I M U S GALACTOSEGALACTOSEtime (dates)
minimal change disease (variant with focal mesangial
two months of tacrolimus therapy, proteinuria was
proliferation with deposition of immunoglobulin
similar to the level before therapy (3.68 g/24 h). We
[Ig]M in the mesangium). Electron microscopy
then added galactose (Fagron, Barsbuttel, Germany)
revealed a thinned glomerular basement membrane,
at a dose of 0.2 g/kg/dose twice a day for one month,
which was considered normal for the boy’s age. Due
after which proteinuria decreased to 1.8 g/24 h two
to failure to induce remission with corticosteroid
months after stopping galactose treatment. Since pro-
treatment, we began immunosuppressive therapy
teinuria repeatedly rose up to 2.5 g/24 h, about six
with cyclophosphamide in October 2002. After three
months later we added galactose once again at the
monthly pulses, proteinuria was still over 2 g/24 h,
same dose, this time for six months. All this time, the
and both the sedimentation rate (SR) and the blood
patient regularly received tacrolimus as well. At
cholesterol level were high. We introduced low-dose
follow-up after three months of galactose treatment,
combination immunosuppressive therapy with meth-
proteinuria slightly decreased to 1.96 g/24 h, but the
ylprednisolone 0.1 mg/kg, cyclophosphamide, aza-
plasma albumin concentration rose to 3.2 g/dL after
thioprine, and indomethacin (all three drugs in doses
previously being constantly below the normal
of 0.3 mg/kg once per day). After about six months of
level. The plasma cholesterol level decreased to
this therapy, proteinuria had slightly decreased, but
5.6 mmol/L compared to previous concentrations
hypercholesterolemia persisted. For this reason, a
between 6.5 and 8 mmol/L. At the last follow-up
statin was added to the therapy regimen. In Novem-
about three months after the second course of galac-
ber 2006, proteinuria was 1.89 g/24 h and combina-
tose treatment, proteinuria was stable at 1.8 g/24 h
tion immunosuppressive therapy was replaced with
and, for the first time, the albumin (3.4 g/dL) and
mycophenolate mofetil (250 mg twice daily). Pro-
cholesterol concentrations (4.1 mmol/L) in the blood
teinuria was transiently decreased to 0.67 g/24 h after
two months, but soon returned to previous levels ofup to 3.63 g/24 h. In June 2008, a renal biopsy was
Case report 2
performed, showing transformation to the perihilar
A 16 1 -year-old girl with a nephrotic syndrome,
variant of focal segmental glomerulosclerosis (33%)
resistant to corticosteroids, was admitted. A renal
with diffuse mesangial immune deposits with pre-
biopsy revealed mesangioproliferative glomerulone-
dominance of C1q and IgG. We discontinued therapy
phritis with C1q nephropathy. The patient was
with mycophenolate mofetil and began therapy with
treated with pulse therapy using corticosteroids,
six monthly pulses of cyclophosphamide. Despite this
which decreased proteinuria from 7.3 g/24 h to 1.5 g/
treatment, proteinuria persisted (up to 3.42 g/24 h),
24 h, but the effect was only transient as the pro-
as did other parameters of nephrotic syndrome. For
teinuria returned to similar levels soon afterwards.
this reason, a repeat biopsy was performed in Febru-
Additionally, severe depression developed after
ary 2009, the result of which was very similar to the
pulse therapy. Therapy with tacrolimus was initiated
previous one, only this time the immunofluorescent
together with tapering of corticosteroids. Despite
deposits were slightly less prominent. We decided to
regular treatment with tacrolimus, consistent with
begin therapy with tacrolimus in March 2009. After
appropriate blood levels of the drug between 5 and
Ther Apher Dial, Vol. 15, No. 3, 2011
Therapeutic Apheresis and Dialysis 2011 International Society for Apheresis
Galactose Therapy for Nephrotic SyndromeTACROLIMUSGALACTOSEtime (dates)
8 mg/L, nephrotic proteinuria persisted and contin-
may depend on FSGS-PF binding to glomerular
ued to remain above 2.5 g/24 h. After six months of
galactose. Galactose inactivates it and seems to lead
tacrolimus treatment, galactose was added at a dose
to its clearance from plasma. In addition, the FSGS-
of 0.2 g/kg/dose twice a day for three months, which
PF–galactose complex may be susceptible to uptake
reduced proteinuria to 0.76 g/24 h, with the plasma
and catabolism by asialoglycoprotein receptors in
albumin concentration being 37 g/L. After the dis-
hepatocytes or macrophages (2). A previous study
continuation of galactose, proteinuria increased
showed that plasmapheresis in patients with FSGS
despite further treatment with tacrolimus. At the last
lowered PFa and decreased proteinuria, and PFa
follow-up, proteinuria was again 2.48 g/24 h one year
was detected in plasmapheresis fluid. Its decrease
after the discontinuation of galactose treatment. The
serum albumin concentration gradually increased
removal of a substance that is primarily confined to
from 3 g/dL during corticosteroid treatment and at
the plasma space and is not rapidly synthesized
the beginning of tacrolimus treatment to 4 g/dL in the
after its removal (5). It seems, therefore, that the
following months (Fig. 2). The serum cholesterol
restoration of PFa is a slow process. Mechanisms
level was also elevated during corticosteroid treat-
other than just simple removal of FSGS-PF from
ment and at the beginning of tacrolimus treatment,
the circulation may contribute to this prolonged
effect. The uptake and catabolism of the FSGS-PF–galactose complex by receptors in the liver is
DISCUSSION
perhaps only one of them. The dose of galactosethat we used was 0.2 g/kg/dose twice a day. An inter-
The addition of galactose to therapy seems to
ventional study is presently recruiting patients with
have induced a partial remission of nephrotic syn-
primary FSGS to determine if the oral administra-
drome in our two patients, which was sustained for
seven years in one of them. To our knowledge, these
are the first reported cases of at least the partial
Previous observations have provided evidence that
success of galactose treatment in children; however,
a glomerular permeability factor can be transferred
a late contribution of tacrolimus to the beneficial
through the placenta, and that it loses its proteinuric
effects of galactose cannot be ruled out. We did not
effect within a few days. In the reported case of tran-
measure the permeability factor activity (PFa), as
sient nephrotic syndrome in the infant of a mother
was done in other reports (2,4), because it is not
who had FSGS, in utero exposure did not cause
available at our institution; however, owing to the
chronic glomerular disease in the neonate. This indi-
clinical and laboratory improvements observed
cated that the molecular size of the factor was smaller
during galactose treatment, we have decided to con-
than that of IgG, which would persist in the infant’s
tinue with it. We assume with high probability that
this factor was present in our patients and had high
The use of galactose as a new therapeutic agent has
activity. The long-term decrease in proteinuria after
also been investigated in other areas of medicine. Its
oral galactose is consistent with the clearance of
successful use in an adult patient was reported for the
FSGS-PF from the plasma. Savin et al. showed that
treatment of the cardiac variant of Fabry’s disease
interaction between FSGS-PF and the glomeruli
2011 The AuthorsTherapeutic Apheresis and Dialysis 2011 International Society for Apheresis
Ther Apher Dial, Vol. 15, No. 3, 2011CONCLUSION
2. Savin VJ, McCarthy ET, Sharma R, Charba D, Sharma M.
Galactose binds to focal segmental glomerulosclerosis perme-
It seems that galactose could be a promising new,
ability factor and inhibits its activity. Tansl Res 2008;151:288–92.
3. Hoyer JR, Vernier JL, Najarian JS et al. Recurrence of idio-
harmless, and relatively inexpensive therapy for the
pathic nephrotic syndrome after renal transplantation. J Am
treatment of resistant nephrotic syndrome, but more
Soc Nephrol 2001;12:1994–2002.
studies are needed. As mentioned, a few case reports
4. DeSmet E, Rioux JP, Ammann H, Déziel C, Quérin S. FSGS
permeability factor-associated nephrotic syndrome: remission
of the successful use of galactose have already been
after oral galactose therapy. Nephrol Dial Transplant 2009;24:
described. It has the potential to reduce proteinuria
as well as to delay the progression to renal failure, but
5. Savin VJ, Sharma R, Sharma M et al. Circulating factor associ-
ated with increased glomerular permeability to albumin in
to the best of our knowledge, this is the first report
recurrent focal segmental glomerulosclerosis. N Engl J Med
about the partial success of galactose treatment of
resistant nephrotic syndrome in children.
6. Moudgil A, Sgambat K. Oral galactose in children with focal
segmental glomerulosclerosis (FSGS). ClinicalTrials.gov identi-fier NCT01113385.
7. Kemper MJ, Wolf G, Müller-Wiefel DE. Transmission of glom-
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Therapeutic Apheresis and Dialysis 2011 International Society for Apheresis